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Dr Richard Hunt
Department of Pathology, Microbiology and Immunology
University of South Carolina School of Medicine



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Figure 1
Acute Viral Hepatitis by Type, United States, 1982-1993
The five viruses described in Chapter Eighteen cause hepatitis. "Infectious hepatitis" is caused by hepatitis A virus (HAV); "serum hepatitis" results from hepatitis B virus (HBV) and the delta agent (HDV). "Non-A, non-B hepatitis" is caused by hepatitis E (HEV) and hepatitis C (HCV) viruses (figure 1). HAV and HEV are transmitted enterically, while HCV, HBV and HDV are transmitted parenterally. There are more than 700,000 cases of viral hepatitis per annum in the United States, of which more than half are asymptomatic. Despite the availability of highly effective vaccines against hepatitis A and hepatitis B, these diseases are among the most reported vaccine-preventable diseases in the United States.



Disease Infectious hepatitis Serum hepatitis Non-A, non-B hepatitis

Post transfusion hepatitis

Delta agent Enteric non-A, non-B hepatitis  
Source Feces Blood and body fluids

Sexual contact

Blood and body fluids

Sexual contact

Blood and body fluids

Sexual contact

Feces Blood and body fluids
Transmission Enteric












Sexual transmission Yes (especially homosexual)          
Chronic infection No Yes Yes Yes No Yes
Incubation period 15 - 20 days 45 - 160  14 - 180 15 - 64 16 - 60 ?
Carcinogenesis No Hepatocellular carcinoma Hepatocellular carcinoma Hepatocellular carcinoma No ?
Cirrhosis No Yes Yes Yes No ?
Severity of disease Usually mild. Very low mortality Sometimes severe

1 -2% mortality

Usually (80%) asymptomatic

Up to 4% mortality

Super-infection with HBV - often very severe with high mortality rate

Co-infection with HBV - often severe

Usually mild except in pregnancy Asymptomatic to mild
Prevention Vaccine Vaccine Behavior Modification

Blood screening

Behavior Modification

HBV vaccine

Safe water

No vaccine

Chemotherapy     Peginterferon/ Ribovirin      
United States chronic infections (total) None 1- 1.25 million 3.5 million 70,000 None  
United States acute infections per year (estimated) 125,000 to 200,000 140,000 to 320,000 35,000 to 180,000 6,000 to 13,000    
United States Deaths per year from fulminant hepatitis 100 150 ? 35 None ?
United States Deaths from chronic liver disease None 5,000 8,000-10,000 1,000    


Figure 2
Hepatitis A virus

Hepatitis A virus (HAV) (figure 2) causes infectious hepatitis which is transmitted via the oral-fecal route as a result of close contact such as in day-care centers. The virus is also spread by sexual contact and in contaminated food. Rarely (in fewer than 1% of cases) is HAV spread by blood products, blood transfusions or intravenous drug use.

This form of hepatitis accounts for about 40-50% of all hepatitis cases (figure 1). The orally ingested virus first enters the bloodstream via the lining of the intestinal tract and then migrates to the liver parenchymal cells. These cells become infected because they have the immunoglobulin-like HAV cellular receptor on their surfaces. The virus replicates rather slowly and is shed into the bile and passed in the stool. The symptoms of HAV and HBV are very similar. There is only one HAV serotype worldwide and humans are the only reservoir.

The most obvious symptom is jaundice. HAV also causes abdominal pain, nausea and diarrhea. In addition, the patient may suffer fatigue and fever. Chronic infections with HAV do not occur but some patients may experience symptoms for up to 9 months.

Acute hepatitis A case definition


There is no evidence for HAV being the cause of liver cancer (hepatocellular carcinoma).
Figure 3
Events in hepatitis A infection CDC
Immune response
Virus particles are found in the bloodstream from three days to five weeks after infection and in the stool from one to five weeks after infection. In the latter part of this period, raised liver enzymes in the bloodstream (e.g. alanine amino transferase) are observed. IgM (which is used in diagnosis) rises soon after the initial infection and peaks at about 5 weeks. Anti-HAV IgG rises later (two to three weeks) (figure 3). There is a cytotoxic T cell and natural killer cell response that kills infected cells. The humoral response is also important in counteracting the virus but most pathological effects of the virus are the result of the immune response rather than the virus itself. Once the patient has cleared the virus, the anti-HAV IgG antibody response gives life-long protection.
Figure 4
Concentration of HAV in various body fluids CDC
There is a prodromal (incubation) phase of between two and eight weeks after infection, following which there is an abrupt onset of symptoms. After about two weeks of infection, virus is detectable in the liver, blood and stool (Feces can contain up to 108 infectious virions per milliliter and are the primary source of HAV) (figure 4). The virus replicates in hepatocytes but little cellular damage ensues. Thus, the symptoms of infectious hepatitis are not caused by the presence of HAV in the liver but by the immunological response of the host to its presence. Initially, patients experience fatigue, pain in the abdomen and nausea and there are elevated levels of liver enzymes in the serum

A few days after the first symptoms, jaundice (icteric symptoms) often occurs; this is particularly noticeable in the sclera. Jaundice is seen in about 60% of adults but far fewer children (up to 20%). There is also dark urine and light stool. Children show lesser symptoms than adults; for example, jaundice is seen among fewer than 10% of children younger than 6 years of age, 40%-50% of older children and 70%-80% of adults.

Almost all (99%) patients make a complete recovery within two to four weeks with no chronic sequelae. In about 0.1% of patients, fulminant hepatitis occurs leading to death in the majority of these patients (about 50-80%). This results from liver failure and encephalopathy. Other rare complications are relapsing hepatitis and cholestatic hepatitis (in which there are very high bilirubin levels). The former, which has symptoms similar to the original infection, usually occurs within three months of the initial HAV infection. In cholestatic hepatitis, liver damage by the virus occurs leading to obstruction of bile secretion. This is most often seen in immuno-compromised patients.

Figure 5
Risk factors for hepatitis A in United States CDC

Figure 6A
Reported Hepatitis A Cases, By Year Northern Plains Indian Reservation, South Dakota, 1968-2002  CDC

Figure 6B
Incidence of hepatitis A in American Indians 1990-2001 CDC


The incidence of HAV infection in the United States has fallen from about 12 cases per 100,000 population in the 1980ís to 2.9 in 2002 (figure 7B). This is largely due to the availability of the vaccine. In 2001, there were 93,000 new HAV infections in the United States. There were an estimated 45,000 acute clinical cases (but many fewer were actually reported). in the United States, hepatitis A outbreaks used to occur in 10 to 15 years cycles. Since transmission is via the oral-fecal route, members of the family of an infected person are most at risk. Community outbreaks are common but in half of all cases no risk factor is identified (figure 5). The infected person is contagious before overt symptoms appear. Many infected persons are asymptomatic (most children and up to a half of infected adults) but still shed infectious virus. In addition, conditions of poor housing and cramped conditions lead to spread of the virus. There are frequent outbreaks in daycare centers that are then transmitted to other family members. The virus is also transmitted as a result of sexual contact, especially homosexual sex and, since it is blood-borne, can be spread by sharing needles during use of intravenous drugs. The virus is very resistant to a variety of agents including low pH, organic solvents and detergents. It is also resistant is temperatures as high as 61 degrees for 20 minutes. Besides direct fecal-oral transmission (such as by contaminated hands), the virus may be spread in contaminated drinking water and where raw sewage is present since the virus can survive for months in fresh or salt water. Particularly problematic is sewage contamination of oysters and other shellfish that are filter-feeders. In developing countries, most people get mild HAV infections as children and then retain life-long immunity. Approximately 30% of the population of the United States is seropositive with a much higher incidence in third world countries.

The highest rates of hepatitis A in the United States are found in Hispanic and Native American populations (figures 6, 7D). The lowest are among Asian Americans. This undoubtedly reflects socio-economic conditions such as crowding and also contact with persons from countries such as Mexico with high HAV infection rates. These factors result in  higher hepatitis A incidence in western states (figure 7A, G, H).

In 1990, hepatitis A incidence was highest in children (figure 7C) with about an equal male to female ratio; however, by 2001, the gender/age incidence had changed markedly with the highest incidence in young to middle aged men (figure 7 I, J). This is because the incidence of hepatitis A has fallen as a result of vaccine use and HAV is now mainly spreading among intravenous drug users and homosexual men.

The virus is found worldwide with the highest levels in under-developed countries (figure 7E). In underdeveloped countries, nearly all children have anti-HAV antibodies indicative of a prior infection and epidemics are rare. In countries with higher levels of sanitation, infection occurs in older individuals and clinical disease is more often seen; very often there are localized outbreaks. In some countries with high hygiene standards (e.g. Scandinavia), clinical disease outbreaks are again rare and hepatitis A is seen primarily in intravenous drug users.

Figure 7

A. Distribution of hepatitis A in the United States by county CDC

B. Reported cases of hepatitis A in the United States 1952-2002 CDC

C. Incidence of hepatitis A by age group 1990-2001 CDC

D. Incidence of hepatitis A by race in United States CDC

E. Global distribution of hepatitis A CDC

G. Hepatitis A incidence in United States.  Comparison of 1987 - 97 average with 2002 CDC

H. States with highest hepatitis A rates CDC

I. Hepatitis A in the United States by age and gender  1990 CDC

J. Hepatitis A in the United States by age and gender  2001 CDC


F. Hepatitis A Incidence, United States,


An ELIZA test for anti-HAV IgM is available. Diagnosis is also made from the symptoms and the clusters of cases that occur. The presence of IgG within the first few weeks of infection suggests a prior infection or vaccination.
There is no treatment. Supportive care should be given. Hepatitis A immune globulin can be administered early after infection (two weeks) and gives some temporary immunity (up to five months).
Improved hygiene is the most important factor in stemming the spread of HAV. Chlorination of water is very effective. Before the present vaccine, passive immunity was obtained using immune gamma globulin which was effective against the disease in most cases if given before infection as prophylaxis or during the early incubation period. The present very effective vaccines (HAVRIX and VAQTA) used in the United States are killed (formalin) virus preparations. The vaccine is given in the first year of life and immunity, probably life-long, results within a month. In adults, the vaccines give protective immunity within one month of vaccination in most recipients. A second dose leads to 100% protection.


ACIP recommendations for vaccination of children Persons for whom the HAV vaccine is recommended Immune globulin information More vaccine information

There is a combined anti-HAV/HBV vaccine approved in the United States for recipients of 18 years and older. It contains Hepatitis A antigen and HBsAg. In other countries, this vaccine is available for children.


Figure 8
Geographic distribution of hepatitis E CDC
Hepatitis E virus (HEV) causes enteric non-A, non-B hepatitis and is transmitted via the oral-fecal route through contaminated drinking water. It is not usually transmitted directly from one patient to another (in contrast to HAV). HEV outbreaks can be extensive and is likely the cause of much of the acute sporadic hepatitis seen in areas where the virus is found (figure 8). In countries of low incidence, HEV infections are usually seen in travelers.

After an incubation 16 to 60 days (with an average of 40 days), typical hepatitis symptoms arise (jaundice, malaise, abdominal pain, nausea etc). Virus may be excreted in the stool for several weeks after the onset of symptoms. There is no evidence for chronic HEV infections but persistence in the population may be the result of a low level of infections between epidemics. In pregnant women the mortality rate is high.
Figure 9
Hepatitis E infection - Typical serologic course CDC
After a prodromal phase of about a month, symptoms occur. Virus is found earlier in the stool . Alanine aminotransferase rises at the same time anti-HEV IgM and IgG. By about two months, elevated alanine aminotransferase diminishes, as does IgM. IgG remains and results in short term immunity (figure 9).

There are no commercially available tests for routine diagnosis
HEV is endemic to many tropical countries where good sanitation is lacking. In the United States less than 2% of the population has anti-HEV antibodies. The source of these infections is not known.

Possibly contaminated drinking water should be avoided as should uncooked food in endemic areas. Immune globulin is not effective if it comes from donors in western countries. There is no vaccine.



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